Inhibitors of Type 4 cyclic AMP phosphodiesterase (PDE4), such as rolipram, produce both antidepressant-like and memory-enhancing effects in preclinical models. Consistent with this, it has been shown that drugs from this class possess clinical antidepressant efficacy, including reversal of cognitive deficits that occur in depression. Ultimately, it may prove possible to dissociate the antidepressant and cognitive effects of PDE4 inhibitors from their other pharmacological effects. To do so will require a better understanding of the roles of the PDE4 subtypes expressed in brain (PDE4A, PDE4B, and PDE4D) in mediating the behavioral effects of PDE4 inhibitors. In addition, the manner in which PDE4 inhibitors interact with two affinity states of the PDE4 molecule (termed the high-affinity and low-affinity rolipram binding sites) to produce their effects on behavior must be elucidated. The proposed experiments will address the neuropharmacological mechanisms by which PDE4 inhibitors produce antidepressant-like and memory-enhancing effects on behavior. In addition they will assess the role of PDE4 in mediating the behavioral effects of proven antidepressant drugs. The specific aims are to: 1) Determine the effects of repeated treatment with antidepressant drugs on the expression of PDE4 subtypes and on high- and low-affinity rolipram binding sites in brain regions of rats and mice; 2) Determine whether the antidepressant-like effects of PDE4 inhibitors depend on intact noradrenergic and serotonergic function; 3) Determine which PDE4 subtypes are involved in mediating the behavioral effects of antidepressants and the antidepressant-like behavioral effects of PDE4 inhibitors; 4) Determine which PDE4 subtypes are involved in mediating the memory-enhancing effects of PDE4 inhibitors; and 5) Determine the contribution of the high- and low-affinity rolipram binding sites to the behavioral and neurochemical effects of PDE4 inhibitors. Completion of the proposed experiments will establish the importance of the individual PDE4 subtypes and the high- and low-affinity rolipram binding sites in the mediation of antidepressant-like and memoryenhancing effects of PDE4 inhibitors. In addition, the role of noradrenergic and serotonergic systems in the mediation of the neuropsychopharmacological effects of PDE4 inhibitors will be elucidated. Overall, such information will aid in the identification of novel pharmacological targets for the pharmacotherapy of depression.